Science

What’s sending kids to hospitals with hepatitis—coronavirus, adenovirus, or both?

Physicians at pediatric liver centers in the United Kingdom have been meeting regularly to work out how best to care for children with a mysterious hepatitis that has afflicted at least 176 children in the United Kingdom and more than 500 worldwide.

But they can’t agree.

“It’s proving immensely difficult to get everyone to agree how on Earth to manage these children,” says Will Irving, a virologist at the University of Nottingham.

At the center of the debate are conflicting theories about what is causing healthy young children to suddenly become jaundiced and fall seriously ill with acute liver inflammation. One hypothesis suggests the damage is being done by adenovirus, a common childhood infection that normally causes coldlike symptoms and could be treated with an antiviral drug. Another suggests the cause is a rogue immune response to previous infection by SARS-CoV-2—which could be treated with immune-suppressing drugs such as steroids. A third hypothesis proposed earlier this week brings them together, suggesting adenovirus infection forms a destructive partnership with SARS-CoV-2 that sets the immune system loose on the liver.

“The clinicians have got a really difficult dilemma,” Irving says. “With a sick child, do you give steroids? Do you give [an antiviral drug]? Do you give both?”

Cases remain rare but some children become seriously ill: About 9% of the 180 affected children in the United States have required liver transplants, according to numbers released today by the U.S. Centers for Disease Control and Prevention (CDC); the agency said earlier that five deaths are under investigation. In the United Kingdom, 11 cases have required transplantation, with no deaths as of 3 May.

Physicians say most cases can be managed with supportive care but urge parents to seek medical care immediately if their child shows a yellowing of the skin and whites of the eyes.

Official bodies including CDC and the UK Health Security Agency (UKHSA) have elevated the adenovirus hypothesis. Infection with adenovirus can cause hepatitis in immune-suppressed children but is not known to do so in healthy kids. But CDC says adenovirus had been found in nearly half of the U.S. cases as of 18 May “and continues to be a strong lead.” The agency’s most recent physician alert urges testing of suspected cases for adenovirus. Adenovirus was also found in 72% of U.K. children with hepatitis who were tested for it through 3 May. And UKHSA, in an announcement updating case numbers last week, said pointedly, “Our investigations continue to suggest there is an association with adenovirus.”

“The fact you have it in over 70% of cases does suggest that it must have a role,” says Deirdre Kelly, a pediatric hepatologist at Birmingham Children’s Hospital, one of a group of technical experts advising UKHSA.

But other scientists and hepatologists say adenovirus could be an innocent bystander. The key question, says Isabella Eckerle, a virologist at the University of Geneva, is “how specific is this finding of low amounts of adenovirus? Would we also find it in healthy kids?”

UKHSA aims to answer a similar question. It is expected to publish today the methodology for a study that will compare adenovirus prevalence in children hospitalized with the mysterious hepatitis with that in children hospitalized for other reasons.

The skeptics note that liver biopsies from the affected children have failed to find cells stuffed with adenovirus, a classic sign of adenoviral hepatitis. They say, sometimes heatedly, that the agencies are overlooking a more likely culprit, SARS-COV-2.

“It is profoundly embarrassing that major scientific bodies in U.S. and U.K. are using such weak circumstantial evidence to distract the public … [from the] likely possibility that recent SARS-CoV-2 infection may be driving the increase in cases,” Farid Jalali, an adult hepatologist in Laguna Hills, California, tweeted recently.

He and others suggest SARS-CoV-2 may trigger an immune-mediated attack on the liver several weeks later, just as other organs can be attacked several weeks after SARS-CoV-2 infection in the condition called multisystem inflammatory syndrome in children (MIS-C).

Only some of the children with hepatitis are currently infected with SARS-CoV-2;in the United Kingdom, the figure was 18%. But a recent CDC study estimated that 75% of U.S. children younger than 12 have been infected, 31% of them between December 2021 and February. A publication by the European Centre for Disease Prevention and Control last week reported evidence of prior SARS-CoV-2 infection in 14 of 19 children with hepatitis. It also showed that most of the cases in Europe have occurred this year, during a large Omicron wave. Only a tiny minority of the affected children were vaccinated against SARS-CoV-2; vaccines are not available for children under 5 years old, the age group in which most cases occur.  

The debate is not academic. It “has everything to do with whether [a] patient stays alive or not,” Jalali said in an interview. If adenovirus is damaging the liver, the powerful antiviral drug cidofovir could be deployed in urgent cases. But if the liver damage results from a sustained immune reaction, immune-suppressing drugs could be lifesaving. You had better not be wrong, Jalali says. “If you mistakenly assume some infectious process is actively causing liver failure, you can’t go near that patient with immune-suppressive drugs,” because they can hobble the body’s ability to fight an active viral infection.

Petter Brodin, a pediatric immunologist and pediatrician at Imperial College London and Moshe Arditi, a pediatric infectious disease physician at Cedars-Sinai Medical Center, last week published a hypothesis knitting the two viruses together.

They point out that to date, 18 of 18 cases tested in the United Kingdom harbored adenovirus-41, a strain of adenovirus that infects the gut, and that SARS-CoV-2 has been found to establish gut reservoirs that persist after acute infection. Brodin and Arditi proposed that after adenovirus infects the gut, SARS-CoV-2 might act as a coconspirator. A small section of the SARS-CoV-2 spike protein that has been shown to prompt a broad, nonspecific activation of T cells might supercharge the immune response to adenovirus, and the rogue immune response might then attack the liver. Such a mechanism, in which a piece of the coronavirus spike protein triggers an immune overreaction, has been implicated in the serious inflammation found in MIS-C.

Brodin urges clinicians investigating children with the unexplained hepatitis to collect stool samples that could confirm intestinal reservoirs of SARS-CoV-2 and test for a hyperactivated immune system. If the hypothesis is confirmed—and Brodin stresses it has not been—he says immunosuppressive therapy would be appropriate. “[If] it’s an out-of-control activation of the immune system, then you need to be very aggressive in shutting down that immune response.”

Jalali, for his part, is worried by a preprint, not yet peer reviewed, posted on 14 May by scientists at Case Western Reserve University. The paper suggests the hepatitis cases reported so far are the tip of an iceberg of liver damage in children following COVID-19 infections. The researchers compared the electronic records of 246,000 1- to-10-year-old children who contracted COVID-19 between March 2020 and March 2022 with those of 551,00 children who contracted other respiratory infections in that period. In the months after infection, the COVID-19 infected children were 2.5 times more likely to have elevated levels of enzymes that indicate liver damage, and 3.3 times more likely to have elevated bilirubin, a pigment in red blood cells normally processed by the liver. That can be a sign of diminished liver function.  

Clare Wenham, a global health policy expert at the London School of Economics whose 4-year-old son was hospitalized with hepatitis earlier this month and treated with supportive care, has been closely following the battling theories of causation. “There just aren’t enough data to really make any firm conclusions yet,” she says. “You’re with your clinicians and they’re like: ‘We just don’t really know … what the trajectory is going to be.’ That’s what’s scary as a parent.”

Wenham’s son, whose symptoms developed several weeks after she and her daughter had COVID-19, did not test positive for SARS-CoV-2 but was positive for adenovirus. He was discharged home on 15 May. But his liver enzymes remain elevated, Wenham says. “He’s still not out of the woods.”

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